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. Author manuscript; available in PMC: 2016 Apr 1.
Published in final edited form as: J Neurochem. 2015 Feb 8;133(2):174–186. doi: 10.1111/jnc.13029

Figure 7. Schematic representation of VPA-induced neuronal cell death.

Figure 7

Our data confirm a VPA-induced necroptotic pathway that initiates with calpain activation and is accompanied by calpain-dependent activation of JNK1, which is responsible for increased RIP-1 expression. Calpain induces Smac/DIABLO expression as well as cleavage and nuclear translocation of AIF. VPA increases nuclear H2AX, which can complex with tAIF to promote chromatinolysis and necroptotic cell death. Smac/DIABLO increase is accompanied by reduced expression of XIAP, further contributing to necroptosis. These pathways are not activated in PC47 cells that have constitutively activated survival pathways. D= days post-VPA-treatment.